Vanin-1 is a cell surface associated, glycosylphosphatidyl inositol (GPI)—anchored protein which is expressed at high levels in kidney, liver and the small intestine. Vanin-1 expression can be up-regulated in multiple cell types under various inflammatory and oxidative stress conditions. Soluble Vanin-1 is found in serum of mice and humans indicating that Vanin-1 can be shed of the cell surface (Rommelaere S, et al. PPARalpha regulates the production of serum Vanin-1 by liver. FEBS Lett. 2013 Nov. 15; 587(22):3742-8). Three Vanin family members have been described in humans (Vanin-1, Vanin-2 and Vanin-3) and these are classified as members of the biotinidase branch of the nitrilase superfamily (Kaskow B J, et al. Diverse biological activities of the vascular non-inflammatory molecules—the Vanin pantetheinases. Biochem Biophys Res Commun. 2012 Jan. 13; 417(2):653-8).
To date the only known substrate for Vanin-1 is pantetheine and it is believed that Vanin-1 acts as the predominant pantetheinase in vivo catalyzing its hydrolysis to produce pantothenic acid (vitamin B5) and cysteamine (Pitari G, et al. Pantetheinase activity of membrane-bound vanin-1: lack of free cysteamine in tissues of vanin-1 deficient mice. FEBS Lett. 2000; 483:149-154). These products impact diverse biological processes. Panthothenic acid is a necessary factor in the synthesis of Coenzyme A (CoA), a cofactor involved in many metabolic processes such as fatty acid synthesis and oxidation of pyruvate. The amino-thiol cysteamine, the second product of Vanin-1 enzymatic reaction, impacts the cellular redox status (Kaskow B J, et al. Diverse biological activities of the vascular non-inflammatory molecules—the Vanin pantetheinases. Biochem Biophys Res Commun. 2012 Jan. 13; 417(2):653-8 and Nitto T, Onodera K. The Linkage between coenzyme A metabolism and inflammation: roles of Pantetheinase. Journal of pharmacological sciences 2013:123: 1-8).
Vanin-1-deficient mice show no developmental defects nor do they show obvious spontaneous phenotype. However, diverse Vanin-1-dependent phenotypes are revealed in situations of metabolic challenge and/or oxidative stress and tissue damage. Vanin-1-deficient mice exhibit resistance to oxidative tissue injury caused by γ-irradiation or by the administration of paraquat which is correlated with significantly increased glutathione levels (Berruyer C, et al. Vanin-1−/− mice exhibit a glutathione mediated tissue resistance to oxidative stress. Mol Cell Biol. 2004; 24:7214-7224). Vanin-1 deficient animals are also protected against multiple mouse models of IBD including DSS (dextran sulfate) and TNBS (trinitrobenzene sulfonate) colitis as evidenced by preserved mucosal barrier and reduced inflammatory infiltrate (Berruyer C, et al. Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor g activity. J Exp Med. 2006; 203:2817-2827 and et al. Vanin-1−/− mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores. J Clin Invest. 2004; 113:591-597). In humans, Vanin-1 expression is significantly increased in the colonic mucosa from IBD patients and functional polymorphisms in the regulatory regions of the Vanin-1 gene are associated with susceptibility to inflammatory bowel diseases (Gensollen T, et. al. Functional polymorphisms in the regulatory regions of the VNN1 gene are associated with susceptibility to inflammatory bowel diseases. Inflamm Bowel Dis. 2013 October; 19(11):2315-25). In addition, patients with ulcerative colitis have an increased risk of developing colorectal cancer and Vanin-1 knock-out mice exhibit drastically reduced incidence of tumors in colitis associated cancer model (Pouyet L, et al. Epithelial vanin-1 controls inflammation-driven carcinogenesis in the colitis-associated colon cancer model. Inflamm Bowel Dis. 2010 January; 16(1):96-104).
Vanin-1 is a key activator for hepatic gluconeogenesis (Chen S, et al. Vanin-1 is a key activator for hepatic gluconeogenesis. Diabetes. 2014 June; 63(6):2073-85. doi: 10.2337/db13-0788. Epub 2014 Feb. 18). Vanin-1 regulates the activation of smooth muscle cells in vitro and development of neointimal hyperplasia in response to carotid artery ligation in vivo. Polymorphysims in VNN1 gene are associated with blood pressure and HDL levels further supporting Vanin-1's role in cardiovascular diseases. Vanin-1 deficiency prevents mice from the development of adrenocortical neoplasia in Sf-1 transgenic mice suggesting a role for Vanin-1 in certain cancers. In the context of infection, Vanin-1 deficiency reduces granuloma formation and tissue damage against Coxiella burnetii, a bacterium that causes 0 fever. Vanin-1 is highly up-regulated in psoriatic skin lesions compared with normal individuals. Vnn-1 gene is also up-regulated in whole blood of patients with pediatric immune thrombocytopenia (ITP) where overexpression of VNN1, is associated with progression to chronic ITP. In addition, elevated Vanin-1 has been detected in urines of patients with multiple renal disorders including systemic lupus erythematosus, nephrotoxicant-induced renal injury and type 2-diabetes (Rommelaere S, et al. PPARalpha regulates the production of serum Vanin-1 by liver. FEBS Lett. 2013 Nov. 15; 587(22):3742-8).
There is a need for novel and potent small molecule compounds which act as inhibitors of vanin-1 enzyme.